Collagen is the single most abundant animal protein in mammals, accounting for up to 30% of all proteins. The collagen molecule, after being secreted by the fibroblast cell, assembles into characteristic fibers responsible for the functional integrity of tissues making up most organs in the body. The skin is the largest organ of the body occupying the greatest surface area within the human body. As age advances and as a result of other noxious stimuli, such as the increased concentration of the ultraviolet part of the electromagnetic spectrum as radiated from the sun, structural integrity and elasticity of skin diminishes.
Crosslinks between adjacent molecules are a prerequisite for this integrity of the collagen fibers to withstand the physical stresses to which they are exposed. A variety of human conditions, normal and pathological, involve the ability of tissues to repair and regenerate their collagenous framework. In the human, 13 collagen types have been identified. Of the different identifiable types, type I is the most abundant in skin where it makes up 80 to 90% of the total collagen connective tissue. This type of collagen, however, is less dynamic in the full-grown individual than its counterparts in which collagen is involved in active remodeling. In this case the normal collagen synthesizing activities in skin is relatively quiescent exhibiting slow, almost negligible, turnover.
The extra-cellular matrix of the various connective tissues, such as skin, consists of complex macromolecules, collagen, elastin and glycosaminoglycans (GAGs). The biosynthesis of these macromolecules involves several specific reactions that are often under stringent enzymatic control. The net accumulation of connective tissues is thus, dependent upon the precise balance between the synthesis and the degradation of the connective tissue components.
Previous disclosures, such as U.S. Pat. No. 4,976,799 and U.S. Pat. No. 5,137,539 have described methods and apparatus for achieving controlled shrinkage of collagen tissue. These prior inventions have applications to collagen shrinkage in many parts of the body and describe specific references to the cosmetic and therapeutic contraction of collagen connective tissue within the skin. In the early 1980's it was found that by matching appropriate laser exposure parameters with these conditions, one had a novel process for the nondestructive thermal modification of collagen connective tissue within the human body to provide beneficial changes. The first clinical application of the process was for the non-destructive modification of the radius of curvature of the cornea of the eye to correct refractive errors, such as myopia, hyperopia, astigmatism and presbyopia. New studies of this process for the previously unobtainable tightening of the tympanic membrane or ear drum for one type of deafness have been made.
In addition to addressing the traditional method of collagen shrinkage wherein the ambient temperature is elevated within the target tissue by about 23 degrees Celsius, the “thermal shrinkage temperature” of collagen, Ts, a novel method for obtaining controlled contraction of collagen at a much lower temperature has been developed. Evidence exists to elevate the mechanical role played by the GAGs in the collagenous matrix. Removing or altering these interstitial chemicals by enzymes or other reagents as disclosed in U.S. Pat. No. 5,304,169 considerably weakens the connective tissue integrity and influences the thermal transformation temperature (Ts). Shrinkage temperature may be defined, therefore, as the specific point at which disruptive tendencies exceed the cohesive forces in this tissue. This temperature, thus, makes this an actual measurement of the stability of the collagen bearing tissue expressed in thermal units.
The cause of wrinkles around the eyelids, mouth and lips is multifactorial: photodamage, smoking and muscular activity such as squinting and smiling all contribute. The end result is a general loss of elasticity, which is a textural skin condition as opposed to a skin redundancy or excess of skin tissue. The surgical injection of reconstituted collagen is commonly used in order to flatten the perioral lines. While oculoplastic surgeons may treat this problem around the eye inappropriately by blepharoplasty, it has been observed that even transconjunctival blepharoplasty for removal of prolapsed retrobulbar fat fails to address the fine periocular lines or wrinkles. Until recently, the main approach to treating these blemishes has been chemical peeling by means of trichloroacetic acid or phenol. Complications of chemical peels may include hypopigmentation, scarring, cicatricial ectropion and incomplete removal of the wrinkles.
Many patients are acutely aware of these cosmetic blemishes as evidenced by the large quantity of money spent each year in the U.S. and abroad upon home and spa remedies for a more youthful appearance. With the advent of laser technology as an alternative to chemical peels or dermabrasion, dermal ablation techniques with both the conventional carbon dioxide lasers and the high energy, short duration pulse waveform CO2 lasers, high tech solutions appear to provide substantial benefits to patients.
CO2 laser resurfacing is not a new technique. CO2 lasers have been used for several years, but regular continuous wave CO2 lasers can cause scarring due to the tissue destruction caused as heat as conducted to adjacent tissue. Even superpulse CO2 lasers produce excessive thermal damage. The Ultrapulse CO2 laser introduced by Coherent, Inc. is an attempt to assuage these drawbacks by offering a high energy, short duration pulse waveform limiting the damage to less than 50 microns allowing a char-free, layer by layer vaporization of the skin tissue.
All of the foregoing procedures depend for their success upon primary damage and the reparative potential induced by the inflammatory process in the tissue. Associated with inflammation are, of course, the four cardinal signs of inflammation of rubor (hyperemia), calor (thermal response), dolor (pain), and tumor or edema or swelling. Coincident with these manifestations is the risk of reduced resistance to infection. One must not forget that these collateral effects accompany a cosmetic enhancement procedure and, for the most part, are not associated with a therapeutic procedure. Therefore, the development of a more efficacious method would be beneficial in this regard.
Various undesirable skin conditions would be improved if the collagen underlying the region of the condition could safely be improved without damage to the overlying region. Wrinkles related to photodamage and acne scars are example of such conditions.
U.S. Pat. Nos. 4,976,709, 5,137,530, 5,304,169, 5,374,265, 5,484,432 issued to Sand, disclose a method and apparatus for controlled thermal shrinkage of collagen fibers in the cornea using light at wavelengths between 1.8 and 2.55 microns. However strong absorption of the laser energy by water limits the penetration depth to the most superficial layers of skin.
The CoolTouch (trademark) 130 laser system by CoolTouch Corp of Auburn, Calif., was first introduced at the Beverly Hills Eyelid Symposium in 1995. It utilizes a laser at a wavelength of 1.32 microns to cause thermally mediated skin treatment. In this device the treatment energy is targeted at the surface of the skin with in depth optical heating of the epidermis, papillary dermis, and upper reticular dermis. The energy is primarily absorbed in tissue water with a skin absorption coefficient of 1.4 cm−1, corresponding to an absorption depth of 0.71 cm. Scattering of the 1.32 micron wavelength light by skin microstructures alters the distribution of light from an exponential attenuation to a more complex distribution, which has much faster attenuation approximating an absorption depth of 0.1 cm. Most of the energy is absorbed in the first 250 microns of tissue. To prevent overheating of the epidermis pulsed cryogen spray precooling is used. U.S. Pat. No. 5,814,040, issued Sep. 29, 1998, describes a dynamic cooling method utilizing pulsed cryogen spray precooling. Skin treated with this device has improved texture and a reduction in wrinkles and scarring due to the long term renewal of dermal collagen without significant skin surface wounding.
U.S. Pat. No. 5,810,801 teaches a method and apparatus for treating a wrinkle in skin by targeting tissue at a level between 100 microns and 1.2 millimeters below the surface, to thermally injure collagen without erythema, by using light at wavelengths between 1.3 and 1.8 microns. The parameters of the invention are such that the radiation is maximally absorbed in the targeted region. The invention offers a detailed description of targeting the 100 micron to 1.2 mm region by utilization of a lens to focus the treatment energy to a depth of 750 microns below the surface. Because of the high scattering and absorption coefficients, precooling is utilized to prevent excess heat build up in the epidermis when targeting the region of 100 microns to 1.2 mm below the surface. The wavelength range of use is 1.3 microns to 1.8 microns in order to avoid the wavelength range of Sand. However the wavelength range of 1.4 to 1.54 microns and the range between 2.06 and 2.2 microns have identical effective attenuation coefficients in skin. Also the range from 1.15 to 1.32 microns has a fairly uniform effective attenuation coefficient in skin of about 6 to 7 cm−1. The effective attenuation length in skin for the range of wavelengths of 1.3 to 1.8 microns varies from 6 cm−1 at 1.3 microns to 52 cm−1 microns, corresponding penetration depths in skin of 200 microns to 2 millimeters. Specific laser and cooling parameters are selected so as to avoid erythema and achieve improvement in wrinkles as the long term result of a new collagen formation following treatment.
Kelly et al, report improvement in skin due to collagen remodeling after treatments with an Nd:YAG laser at 1.32 microns and cryogen spray precooling. In this case the method was designed to provide a series of treatments with parameters selected to produce erythema and mild edema, with some improvement in facial rhytids several months following a series of treatments. However, there is a risk of pigmentary change or transient pitted scarring because of the high fluence level of the laser, greater than 30 joules per square centimeter in 20 millisecond exposures, and the high level of pulse cryogen cooling.
Mucini et al. reported effective dermal remodeling using a 980 nm diode laser with a spherical handpiece which focused irradiation into the dermis avoiding the high scattering and absorption characteristic of longer wavelengths. The device requires a small lens of a few millimeters in contact with skin and results in a slow procedure when used for facial areas.
Ross et al., reported the use of an Erbium:YAG laser operating at a wavelength of 1.54 microns fired in a multiple pulsed mode has been described for eliciting changes in photodamaged skin. A chilled lens in contact with skin at the treatment site was used in an attempt to spare the epidermis. Treatment occurred during a period of several seconds with a sequence of cooling and heating with the laser and handpiece. At 1.54 microns the optical penetration depth 0.55 mm and the authors reported that the surface must be chilled before the laser exposure requiring a complex method of cooling and laser exposure. The authors state that a more superficial thermal injury may be needed than could be achieved, and that there are increased patient risks because it would demand more accurate and precise control of heating and cooling.
Bjerring et al, reported the use of a visible light laser, operating at 585 nm wavelength, to initiate collagenesis following interaction of laser energy with small blood vessels in skin.
Other methods of creating subepidermal wounding may utilize electrical current, ultrasonic energy or non-coherent light sources. In all of these methods, including those using lasers, collagen remodeling is a long-term minimal response to the application of energy. Since the objective is a non-invasive or minimally invasive procedure the stimulation of collagenesis must be below the threshold for creating an open wound, resulting in a minimal treatment.
U.S. Pat. No. 5,599,788 describes a method of producing recombinant transforming growth factor .beta.-induced H3 protein and the use of this protein to accelerate wound healing. The protein is applied directly to a wound or is used to promote adhesion and spreading of dermal fibroblasts to a solid support such as a nylon mesh which is then applied to the wound.
It is heretofore unknown to combine the adverse effect caused by excessive photothermal, mechanical or other type of energy applied to skin or other tissue coupled with a topical or other administration of growth factor(s) or wound healing factor(s) in order to amplify the natural stimulation of growth or collagenesis caused by the wound.